Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].

Absorption, Distribution and Excretion
Completely absorbed within 3–6 hours. In healthy individuals, ammonium chloride is almost completely absorbed after oral administration. Only 1% to 3% of the dose is excreted in feces. Excretion: Urine. No data found. Based on accidental human exposure, after oral administration, ammonium chloride is rapidly absorbed from the gastrointestinal tract and completely absorbed within 3–6 hours. Only 1% to 3% of the dose is excreted in feces. Significant first-pass metabolism occurs in the liver. In animals, after repeated oral administration, ammonium chloride readily enters the body, and its primary target organ for toxicity is the kidneys. Ammonium chloride is effectively absorbed from the gastrointestinal tract… In healthy individuals, ammonium chloride is almost completely absorbed after oral administration. Only 1% to 3% of the dose is excreted in feces. After oral administration, ammonium chloride is rapidly absorbed from the gastrointestinal tract and completely absorbed within 3–6 hours. However, oral ammonium chloride preparations are no longer commercially available in the United States.
After oral administration of 9 mg/kg body weight of ammonium chloride to healthy male and female volunteers, approximately half of the subjects experienced a transient increase in blood ammonia levels. Patients with cirrhosis showed a greater and longer-lasting increase in blood ammonia levels, and higher baseline levels. This confirms significant first-pass metabolism of ammonium chloride in the liver.
Metabolism/Metabolites
Ammonium ions are converted to urea in the liver; chloride ions replace bicarbonate ions.
When ammonium ions are converted to urea, the released hydrogen ions react with bicarbonate ions and other buffers in the body…chloride ions replace bicarbonate ions; the latter are converted to carbon dioxide…the chloride load on the kidneys increases, and a significant portion of chloride ions, along with an equal amount of cations…and an isotonic amount of water are not reabsorbed.
The toxicity of ammonium chloride depends on the ammonia that enters the organism (and subsequently the cells). This substance is readily absorbed from the gastrointestinal tract and used in the liver to synthesize amino acids and proteins. When ammonium ions are converted to urea, the released hydrogen ions react with bicarbonate ions to produce water and carbon dioxide. Chloride ions replace bicarbonate ions. Chloride ions enter the kidneys. Increased extracellular chloride concentration increases renal tubular load. Increased electrolyte and water excretion leads to extracellular fluid loss and promotes edema fluid mobilization. Ammonium chloride is metabolized in the liver to produce urea and hydrochloric acid. Male Sprague-Dawley rats were administered 1000 μmol (15)N ammonium chloride by gavage for 5 consecutive days. The results showed that small but significant excess (15)N nitrates were excreted in the urine for 5 days during and after treatment. A total of 0.28 ± 0.03 μmol of excess (15)N nitrates (mean ± standard error) were recovered per rat, indicating a conversion rate of approximately 0.0080% from ammonia to nitrates. Biological half-life unknown.

Toxicity Summary
Identification and Uses: Ammonium chloride is a white, fine or coarse crystalline powder. It is a good fertilizer for important rainy season crops, especially rice. It is not currently registered for use in the United States, but approved pesticide uses may change periodically, so it is essential to consult federal, state, and local authorities for currently approved uses. Ammonium chloride is also used as a flux in zinc and tin plating; in electroplating and the electrolytic refining of zinc; as an etching solution in printed circuit board manufacturing; in dry-cell and luxch batteries; in explosives manufacturing; as a flame retardant; as a curing agent for formaldehyde-based adhesives; and as a mordant in dyes and printing. It is also used in pharmaceuticals, particularly as a diuretic and expectorant. Human Exposure and Toxicity: Potential symptoms of excessive exposure to its fumes include eye, skin, and respiratory irritation; cough, difficulty breathing, and pulmonary allergies. High doses of ammonium chloride can cause metabolic acidosis secondary to hyperchloremia, especially in patients with impaired renal function. Other adverse reactions to ammonium chloride overdose include rash, headache, hyperventilation, bradycardia, progressive somnolence, confusion, and alternating periods of excitement and coma. Additionally, there are reports of hypocalcemic tetany, hyperglycemia, glycosuria, muscle twitching, hyperreflexia, and abnormal electroencephalograms (EEGs). These adverse reactions are mostly secondary to ammonia poisoning, caused by the liver's inability to convert ammonium ions into urea. Because rapid intravenous injection may increase the risk of ammonia poisoning, ammonium chloride should be administered slowly intravenously to allow the liver to metabolize the ammonium ions. Patients receiving ammonium chloride treatment should be closely monitored for signs and symptoms of ammonia poisoning, such as pallor, sweating, irregular breathing, vomiting, bradycardia, arrhythmias, focal or generalized convulsions, asterixis, tonic-clonic seizures, and coma. Animal experiments: In mice, acute intravenous exposure to ammonium chloride resulted in hyperventilation and clonic movements, sometimes accompanied by tonic-spreading convulsions, but usually manifested as deep coma; convulsions occurred before death, but survivors recovered completely and rapidly. Transient hypoxia exacerbated this syndrome. In rabbits, replacing body fluids with a 1% ammonium chloride solution caused significant iris congestion, but the eyes almost returned to normal the next day, and fully recovered the following day. Ingestion of approximately 500-1000 mg/kg body weight/day of ammonium chloride in mice, guinea pigs, rats, rabbits, and dogs for 1 to 8 days induced metabolic acidosis. Pulmonary edema, central nervous system dysfunction, and kidney damage have been reported after ammonium chloride ingestion. Ammonium chloride also causes changes in calcium and bone metabolism in various animals. Specific toxic effects, such as renal hypertrophy, were found in rats with ammonium chloride added to their diet. Other salts (such as ammonium citrate or sodium chloride) did not induce these effects. Rabbits administered 16.2 g/rabbit of ammonium chloride orally twice daily showed renal tubular cell swelling and nucleolysis. In mice, adding 1/6 molar concentration of ammonium chloride to drinking water after day 7 of gestation resulted in smaller offspring but no congenital defects. In another study, mice administered 600 mg/kg of the drug orally at 8:00 AM and 10:00 AM, and at 12:00 PM and 1:00 PM on day 10 of gestation, resulting in a 7% incidence of congenital digit omission in offspring. Ames tests using Salmonella Typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 were negative regardless of metabolic activation. Ames tests using Escherichia coli strain WP2uvrA were also negative regardless of metabolic activation. Ecotoxicity studies: Four simultaneous early-life-stage ammonia toxicity tests were conducted on smallmouth bass at four different pH levels, ranging from 6.6 to 8.7. Embryos were exposed to ammonium chloride solution from 2-3 day old for 32 days. The study found that the growth-inhibiting concentration range was 0.056 mg/L at pH 6.60 and 0.865 mg/L at pH 8.68. 180 silver salmon were exposed to ammonium chloride solution at concentrations of 0.019–0.33 mg/L for 91 days. In the high-dose group, the fish showed significantly reduced hemoglobin content and hematocrit, and an increased proportion of immature red blood cells. A series of studies were conducted on the key species, Eisenia fetida, in solid-phase pilot and full-size apparatuses. Solid-phase experiments showed that ammonium chloride has relatively low toxicity to ammonium, with an LC50 of 1.49 g/kg.

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Protein binding
No data found.

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Interactions
Cisplatin (cis-diamminodichloroplatin II, CDDP) is a drug that exerts its therapeutic effect by inducing apoptosis. However, its side effects and drug resistance limit its clinical application. Extensive research has focused on the drug-target interactions, cell pharmacology, and pharmacokinetics of cisplatin. To minimize toxicity and overcome cisplatin resistance, new therapeutic strategies for combination therapy with cisplatin need to be developed. Ammonium chloride (NH4Cl) has wide applications in various fields, but its combination with cisplatin for the treatment of cancer cells has not been previously reported. In this study, we found that ammonium chloride (NH4Cl) may be an effective drug for the combination therapy of cisplatin with HeLa human cervical cancer (HCC) cells. Cisplatin inhibits cell growth and induces apoptosis and DNA double-strand breaks. Furthermore, ammonium chloride treatment increases the apoptosis rate and caspase-3 activation levels. Notably, we found that ammonium chloride treatment enhances cisplatin-induced H2AX phosphorylation levels. In summary, our data indicate that ammonium chloride enhances the cytotoxicity of cisplatin by increasing DNA damage in HeLa liver cancer cells. High doses of ammonium chloride acidify urine, thereby reducing the ionization of chlorpropamide (diabinese) and decreasing its urinary excretion. Ammonium chloride tends to acidify urine, thus increasing the likelihood of aminosalicylic acid crystalluria. It is speculated that the inhibitory effect of spironolactone on aldosterone may impair the kidney's ability to secrete hydrogen ions, and this combination, in the presence of acidifying doses of ammonium chloride, may lead to systemic acidosis. For more complete data on ammonium chloride interactions (16 items in total), please visit the HSDB records page.

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Non-human toxicity values
Oral LD50 in rats: 1650 mg/kg
Intramuscular LD50 in rats: 30 mg/kg
Intravenous LD50 in rats: 7-10 mmol/kg
Oral LD50 in mice: 1300 mg/kg body weight
For more complete non-human toxicity data on ammonium chloride (8 types in total), please visit the HSDB record page.

[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019 Feb;53(2):211-216.

Ammonium chloride is a white crystalline solid, readily soluble in water (solubility 37%). Its main hazard lies in its environmental threat. Immediate measures should be taken to limit its environmental release. Ammonium chloride can be used to manufacture other ammonium compounds, as a flux, fertilizer, and for many other purposes. Ammonium chloride is an inorganic chloride whose counterion is the ammonium ion. It can act as a ferroptosis inhibitor. It is both an inorganic chloride and an ammonium salt. Ammonium chloride is an inorganic compound with the chemical formula NH₄Cl. It is extremely soluble in water, forming a weakly acidic solution. Ammonium chloride is a systemic and urinary acidifier. Ammonium chloride helps maintain pH and has a mild diuretic effect. This acidic salt can also act as an expectorant by stimulating mucous membranes, used to relieve coughs. An acidifier with expectorant and diuretic effects. Also used in etching and battery manufacturing, as well as electroplating flux. See also: Ammonium chloride; Kalamifene ethanesulfonate (ingredient); Ammonium chloride; Potassium iodide (ingredient); Ammonium chloride; Chlorine dioxide (ingredient)... See more...

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Drug Indications
1. Expectorant in cough syrups. 2. Ammonium ions (NH4+) in the body play an important role in maintaining acid-base balance. The kidneys use ammonium ions (NH4+) instead of sodium ions (Na+) to bind with fixed anions to maintain acid-base balance, especially as a homeostatic compensation mechanism in metabolic acidosis. The therapeutic effect of ammonium chloride depends on the kidneys' ability to excrete excess fixed anions using ammonia and the liver's ability to convert ammonia into urea, thereby releasing hydrogen ions (H+) and chloride ions (Cl-) into the extracellular fluid. Ammonium chloride injection (USP), diluted with isotonic sodium chloride injection, can be used to treat the following patients: (1) hypochloremia and (2) metabolic alkalosis.
Mechanism of Action
Ammonium chloride increases acidity by increasing hydrogen ion concentration. Due to its irritant effect on the bronchial mucosa, ammonium chloride can be used as an expectorant. This action promotes the production of respiratory secretions, thus aiding in effective coughing.
The acidity of ammonium chloride stems from its dissociation into ammonium cations and chloride anions. In patients with normal liver function, ammonium cations are converted to urea in the liver, releasing hydrogen ions, which react with bicarbonate ions to produce water and carbon dioxide. Chloride anions bind to fixed bases in the extracellular fluid, thereby reducing the body's alkaline reserves.
The end result is chloride ions displacing bicarbonate ions. This chloride ion displaces bicarbonate ions, altering the bicarbonate-to-carbonic acid ratio in the body, leading to acidosis. Increased chloride ion concentration in the extracellular fluid increases the load on the renal tubules, and a significant amount of chloride ions cannot be reabsorbed. These anions are excreted along with cations and water. Sodium is the primary excreting cation; however, potassium excretion may also increase to some extent. Ammonium chloride increases the excretion of extracellular electrolytes and water, leading to net loss of extracellular fluid and promoting the mobilization of edema fluid.

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Therapeutic Uses
MeSH Title: Diuretic, Expectorant
Ammonium chloride can be used as a systemic acidifier to treat metabolic alkalosis caused by chloride loss due to vomiting, gastric aspiration, gastric fistula drainage, and pyloric stenosis. Ammonium chloride has also been used to treat chloride depletion caused by diuretics. For patients with hypokalemia, solutions containing isotonic or hypotonic sodium chloride and potassium chloride are generally more effective than ammonium chloride. Ammonium chloride has also been used to treat alkalosis caused by overuse of alkalizing agents. Ammonium chloride has been used in a variety of conditions to induce early acidosis, thereby promoting diuresis, especially in cases of edema associated with hypochloremia. Due to its limited duration of effectiveness, ammonium chloride has limited value as a diuretic when used alone. However, it can be used for short-term treatment to relieve temporary edema, bloating, and/or fullness associated with premenstrual and menstrual periods, when used alone or in combination with xanthine diuretics (such as caffeine and pamabrom). Ammonium chloride is also used to treat Meniere's disease due to its diuretic effect.
Medication (Veterinary): As a urine acidifier, it can increase urine flow rate when administered in high doses. Reduces the incidence of urinary calculi in cattle and sheep. Increases intestinal acidity, thereby increasing calcium absorption, and is used to prevent postpartum hypocalcemia in cattle. Bronchial secretion irritant and diluent.
For more complete data on the therapeutic uses of ammonium chloride (11 in total), please visit the HSDB record page.
Drug Warnings
Ammonium salts are contraindicated in patients with hepatic or renal impairment.
Patients receiving ammonium chloride treatment should be closely monitored for signs and symptoms of ammonia toxicity, such as pallor, sweating, irregular breathing, vomiting, bradycardia, arrhythmia, focal or generalized convulsions, asterixis, tonic-clonic seizures, and coma.
For patients with secondary metabolic alkalosis due to intracellular potassium depletion, ammonium chloride alone cannot sustainably correct hypochloremia; potassium chloride must be administered concurrently in these patients.
Ammonium chloride should be used with caution in patients with pulmonary insufficiency or cardiogenic edema. This drug should not be used in patients with primary respiratory acidosis or high levels of total carbon dioxide and buffer bases.
For more complete data on drug warnings for ammonium chloride (12 in total), please visit the HSDB record page.
Pharmacodynamics

Systemic acidifier. In the liver, ammonium chloride is converted to urea, releasing hydrogen ions (lowering pH) and chloride ions.

CLD415N

58.51

57.028

99011-95-7

54450-56-5 ((ammonium)HCl2));12125-02-9 (Parent)

25517

Colorless crystals or crystalline masses, or white, granular powder
Colorless cubic crystals
A white, fine or coarse, crystalline powder
Finely divided, ... white particulate dispersed in air. /Ammonium chloride fume/

340ºC (subl.)(lit.)

1.125

1

1

0

2

0

0

NLXLAEXVIDQMFP-UHFFFAOYSA-N

InChI=1S/ClH.H3N/h1H;1H3

azanium;chloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)